7.6.6 Decanulation and administration of protamine

The sequence for decanulation after bypass is: cardioplegia cannula - venous cannula - aortic cannula. In case of separate cannulation of the two vena cava, one of the cannulas is often removed before pump exit to improve venous return to the RA. As long as the arterial cannula is in place, the perfusionist can easily refill the patient in case of blood loss, but this facility can lead to acute volume overload, which is visible in the surgical field by the sudden dilation of the DV. The blood pressure must be lowered momentarily for aortic decanulation (MAP 50 mmHg), otherwise the closure bursa may tear the wall.

After careful review of the operative findings on TEE, the right atrium can be decannulated and administration of protamine can begin. Usually the first half of the dose is injected slowly (maximum 50 mg/min) via a peripheral venous route, then the aortic cannula is removed and the second half of the protamine is given. This reduces bleeding during arterial decanulation and prevents thrombus formation in the aorta. If the arterial cannula is in the femoral or subclavian position, protamine is not started until the circulation in the artery is fully restored. As soon as protamine administration has begun, the aspirations on the ECC machine are stopped and the lost aspirations and the CellSaver™ are switched. This is because clots can form in the reservoir and oxygenator, demanding the circuit to be changed in case an acute problem requires a return on pump.

Protamine, originally extracted from salmon sperm and now produced by genetic engineering, is a positively charged polycationic molecule that forms stable complexes with heparin, which is negatively charged. It dissociates heparin-antithrombin complexes. Its plasma half-life is 7 minutes. One mg of protamine (100 IU) neutralises 1 mg of heparin (100 IU). Usually, a dose of protamine is given that is 80% of the heparin dose. An ACT taken 5 minutes after the end of the protamine should be within ± 10% of the starting value. Unfortunately, the relationship between heparin level and post-ECC ACT is non-linear and poorly performing. Dosing based on the patient's actual heparin level (Hepcon/HMS™ system), on thromboelastography (HEPTEM) or on a pharmacokinetic algorithm leads to lower amounts (protamine/heparin ratio 0.5-0.8:1) and thereby reduces the hypocagulability, fibrinolysis and platelet dysfunction generated by protamine (see below) [1]. Procoagulant agents (tranexamic acid, fibrinogen, clotting factors, thrombocytes, etc) are only infused after the protamine has worn off. A thromboelastogram (ROTEM™) is used to objectify the needs in case of persistent coagulopathy.

Protamine has several immediate side effects, the incidence of which varies from 1 to 13% of cases (mean 2.6%) [1,3,4].

• Histamine release, which is characterised by significant vasodilatation with a decrease in preload and afterload; it is directly proportional to the speed of administration (type I reaction), which is why it is recommended to infuse protamine diluted in 100 mL 0.9% NaCl over 10 minutes. It is very often necessary to accelerate the infusions and to give a vasoconstrictor (neosynephrine or noradrenaline) to counteract this effect.
• Pulmonary hypertension; heparin-protamine complex triggers the release of thromboxane A2, which is a pulmonary vasoconstrictor; PAP rises by 25-50%.
• Antigen-antibody reaction (IgG and IgE) (type II reaction); rarer, this occurs in diabetics treated with insulin stabilised with protamine (protamine-Zn), in re-operated patients who have previously received protamine, in fish-allergic patients, and in vasectomized men.
• Anaphylactoid reaction triggered by the heparin-protamine complex by directly activating the classical complement pathway (C4a) without the intermediary of an antigen-antibody reaction (type III reaction, which occurs in 1.5% of cases). The clinical picture is that of a fulminant anaphylactic reaction with profound hypotension; the massive release of thomboxane, triggers pulmonary hypertension and bronchoconstriction which can be catastrophic. Treatment includes hydrocortisone, prostaglandin E1 and vasoconstrictors (noradrenaline, vasopressin, methylene blue). In extreme cases, immediate management is to return to bypass surgery and then restart weaning when systemic and pulmonary haemodynamics are controlled; heparin is not antagonised, which involves considerable blood loss.
• In the absence of heparin, or in excess of heparin (protamine/heparin ratio > 1.3:1), protamine has an anticoagulant effect by three different mechanisms. It causes thrombocytopenia and a decrease in platelet aggregability of about 50%; it inhibits the activation of factors V and VII; it induces fibrinolysis [1]. Blood loss increases by 26% when the heparin:protamine ratio is 1.3 instead of 0.8 [5].

Protamine has a direct cardiotoxic effect that can decrease systolic performance by 75% [7]. Patients are sensitised to protamine by previous cardiovascular surgery or by insulin containing protamine as a stabiliser; patients allergic to fish protein are likely to develop a violent reaction [2]. Patients at risk can be anticoagulated with bivalirudin, whose effect is not reversed by protamine, or operated on with pre-heparinised bypass grafts and reduced systemic heparinisation (100 IU/kg), which may avoid the need for protamine [6]. A steroid dose during bypass surgery (500 mg methylprednisolone) and a very slow injection (infusion over 20 minutes) via a peripheral route may decrease the intensity of the reaction in an allergic patient.

© CHASSOT PG, GRONCHI F, April 2008, last update, December 2019

References

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2. FINLEY A, GREENBERG C. Heparin sensitivity and resistance: management during cardiopulmonary bypass. Anesth Analg 2013; 116:1210-22
3. KIMMEL SE, SEKERES M, BERLIN JA, et al. Mortality and adverse events after protamine administration in patients undergoing cardiopulmonary bypass. Anesth Analg 2002; 94:1402-8
4. LOWENSTEIN E, ZAPOL WM. Protamine reactions, explosive mediator release and pulmonary vasoconstriction. Anesthesiology 1990; 73:373-8
5. MEESTERS  MI, VEERHOEK D, DE LANGE F, et al. Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery. Thromb Haemost 2016; 116:251-61
6. MUKADAM ME, PRITCHARD D, RIDDINGTON D, et al. Case 7-2001. Management during cardiopulmonary bypass of patients with presumed fish allergy. J Cardiothorac Vasc Anesth 2001; 15:512-9
7. PEVNI D, FROLKIS I, IAINA A, et al. Protamine cardiotoxicity and nitric oxide. Eur J Cardiothorac Surg 2001; 20:147-52